Novel azole-urea hybrids as VEGFR-2 inhibitors: Synthesis, in vitro antiproliferative evaluation and in silico studies

dc.authorscopusid 58622062100
dc.authorscopusid 57190582389
dc.authorscopusid 57208031609
dc.authorscopusid 24400636500
dc.authorscopusid 58396726400
dc.authorscopusid 6506158277
dc.authorscopusid 26638740000
dc.contributor.author Yelekçi, Kemal
dc.contributor.author Kulabaş, N.
dc.contributor.author Erdoğan, Ö.
dc.contributor.author Çevik, Ö.
dc.contributor.author Dere, D.
dc.contributor.author Yelekçi, K.
dc.contributor.author Danış, Ö.
dc.contributor.other Molecular Biology and Genetics
dc.date.accessioned 2023-10-19T15:05:13Z
dc.date.available 2023-10-19T15:05:13Z
dc.date.issued 2023
dc.department-temp Shirzad, M.M., Department of Chemistry, Faculty of Science, Marmara University, İstanbul, 34722, Turkey; Kulabaş, N., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, İstanbul, 34854, Turkey; Erdoğan, Ö., Department of Medical Biochemistry, Medical Faculty, Gaziantep Islam Science and Technology, Gaziantep, 27010, Turkey; Çevik, Ö., Department of Biochemistry, Faculty of Medicine, Adnan Menderes University, Aydın, 09010, Turkey; Dere, D., Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, İstanbul, Turkey; Yelekçi, K., Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, İstanbul, Turkey; Danış, Ö., Department of Chemistry, Faculty of Science, Marmara University, İstanbul, 34722, Turkey; Küçükgüzel, İ., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Fenerbahçe University, İstanbul, 34758, Turkey en_US
dc.description.abstract The vascular endothelial growth factor receptor-2 (VEGFR-2) is a receptor tyrosine kinase known to be abnormally expressed in various malignant tumors, including breast cancer, and is considered one of the most important contributors to tumor angiogenesis. Sorafenib is one of many VEGFR-2 inhibitors that have received approval for clinical use from the US FDA in recent years. Accordingly, in this study, the synthesis of two new pyrazoles, six 1,3,4-oxadiazoles, four 1,3,4-thiadiazoles, and ten 1,2,4-triazole-3-thione derivatives having structural characteristics similar to sorafenib was carried out. A preliminary screening of synthesized compounds and known inhibitors sorafenib and staurosporine at 10 µM concentration on in vitro activity of VEGFR-2 was performed, and compounds 10c, 8a, and 11 g were identified as the most potent derivatives with% VEGFR-2 residual activities lower than 30%, and dose-dependent inhibition studies was carried out to determine the IC50 values of these inhibitors. Compound 10c was found to be the most potent inhibitor of VEGFR-2 activity with an IC50 value of 0.664 µM. The anti-proliferative activity of synthesized derivatives was assessed against a breast carcinoma (MCF-7) cell line, a triple negative human breast adenocarcinoma (MDA-MB-231) cell line, and noncancerous fibroblast cells (L929). Compound 8a displayed superior activity when compared to sorafenib against MCF-7 (7.69 fold) and MDA-MB-231 (1.52 fold) cell lines while displaying 3.75-fold less toxicity against the normal L929 cell line. Annexin V binding assay revealed that compound 8a significantly increased early and late apoptosis in MCF-7 cells and late apoptosis and necrosis in MDA-MB-231 cells. Computational studies such as molecular docking and ADMET evaluation were performed to elucidate the binding interactions and drug-likeness of the synthesized compounds. The results indicate that compound 8a could be a promising candidate for the development of a novel anti-angiogenic and anti-proliferative agent. © 2023 en_US
dc.description.sponsorship Marmara Üniversitesi: FENC-DRP-170419-0127 en_US
dc.description.sponsorship This work was supported by Marmara University Scientific Research Fund, Türkiye through Project FENC-DRP-170419-0127. en_US
dc.identifier.citationcount 0
dc.identifier.doi 10.1016/j.molstruc.2023.136448 en_US
dc.identifier.issn 0022-2860
dc.identifier.scopus 2-s2.0-85172449865 en_US
dc.identifier.scopusquality Q2
dc.identifier.uri https://doi.org/10.1016/j.molstruc.2023.136448
dc.identifier.uri https://hdl.handle.net/20.500.12469/4745
dc.identifier.volume 1294 en_US
dc.identifier.wosquality N/A
dc.khas 20231019-Scopus en_US
dc.language.iso en en_US
dc.publisher Elsevier B.V. en_US
dc.relation.ispartof Journal of Molecular Structure en_US
dc.relation.publicationcategory Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı en_US
dc.rights info:eu-repo/semantics/closedAccess en_US
dc.scopus.citedbyCount 5
dc.subject 1,2,4-triazole-3-thione en_US
dc.subject 1,3,4-oxadiazoles en_US
dc.subject 1,3,4-thiadiazoles en_US
dc.subject Anti-cancer en_US
dc.subject Pyrazole en_US
dc.subject VEGFR-2 inhibitor en_US
dc.subject Amino acids en_US
dc.subject Binding energy en_US
dc.subject Cell culture en_US
dc.subject Diagnosis en_US
dc.subject Diseases en_US
dc.subject Tumors en_US
dc.subject Urea en_US
dc.subject 1,2,4-triazole-3-thione en_US
dc.subject 1,3,4-oxadiazole en_US
dc.subject 1,3,4-thiadiazole en_US
dc.subject Anti-cancer en_US
dc.subject Oxadiazoles en_US
dc.subject Pyrazoles en_US
dc.subject Thiadiazoles en_US
dc.subject Thiones en_US
dc.subject Vascular endothelial growth factor receptor en_US
dc.subject Vascular endothelial growth factor receptor-2 inhibitor en_US
dc.subject Cell death en_US
dc.title Novel azole-urea hybrids as VEGFR-2 inhibitors: Synthesis, in vitro antiproliferative evaluation and in silico studies en_US
dc.type Article en_US
dspace.entity.type Publication
relation.isAuthorOfPublication 9407938e-3d31-453b-9199-aaa8280a66c5
relation.isAuthorOfPublication.latestForDiscovery 9407938e-3d31-453b-9199-aaa8280a66c5
relation.isOrgUnitOfPublication 71ce8622-7449-4a6a-8fad-44d881416546
relation.isOrgUnitOfPublication.latestForDiscovery 71ce8622-7449-4a6a-8fad-44d881416546

Files

Original bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
4745.pdf
Size:
4.76 MB
Format:
Adobe Portable Document Format
Description:
Tam Metin / Full Text